The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch ...repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair–deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.
BACKGROUND
Hepatocellular carcinoma (HCC) incidence has been increasing in the United States for several decades; and, as the incidence of hepatitis C virus (HCV) infection declines and the ...prevalence of metabolic disorders rises, the proportion of HCC attributable to various risk factors may be changing.
METHODS
Data from the Surveillance, Epidemiology, and End Results‐Medicare linkage were used to calculate population attributable fractions (PAFs) for each risk factor over time. Patients with HCC (n = 10,708) who were diagnosed during the years 2000 through 2011 were compared with a 5% random sample of cancer‐free controls (n = 332,107) residing in the Surveillance, Epidemiology, and End Results areas. Adjusted odds ratios (ORs) and PAFs were calculated for HCV, hepatitis B virus (HBV), metabolic disorders, alcohol‐related disorders, smoking, and genetic disorders.
RESULTS
Overall, the PAF was greatest for metabolic disorders (32%), followed by HCV (20.5%), alcohol (13.4%), smoking (9%), HBV (4.3%), and genetic disorders (1.5%). The PAF for all factors combined was 59.5%. PAFs differed by race/ethnicity and sex. Metabolic disorders had the largest PAF among Hispanics (PAF, 39.3%; 95% confidence interval CI, 31.9%‐46.7%) and whites (PAF, 34.8%; 95% CI, 33.1%‐36.5%), whereas HCV had the largest PAF among blacks (PAF, 36.1%; 95% CI, 31.8%‐40.4%) and Asians (PAF, 29.7%; 95% CI, 25.9%‐33.4%). Between 2000 and 2011, the PAF of metabolic disorders increased from 25.8% (95% CI, 22.8%‐28.9%) to 36% (95% CI, 33.6%‐38.5%). In contrast, the PAFs of alcohol‐related disorders and HCV remained stable.
CONCLUSIONS
Among US Medicare recipients, metabolic disorders contribute more to the burden of HCC than any other risk factor, and the fraction of HCC caused by metabolic disorders has increased in the last decade. Cancer 2016;122:1757‐65. Published 2016. This article is a U.S. Government work and is in the
public domain in the USA..
Although major risk factors for hepatocellular carcinoma are known, the contribution of each to the hepatocellular carcinoma burden in the United States is not well understood. This analysis of Surveillance, Epidemiology, and End Results‐Medicate data indicates that, between 2000 and 2011, the attributable risk of metabolic disorders was consistently higher than that of any other factor, including hepatitis C virus infection, excessive alcohol consumption, smoking, and hepatitis B virus infection.
Summary Current systemic treatment options for patients with hepatocellular carcinoma (HCC) are limited to sorafenib. With the recent FDA approval of the second PD1-PD-L1 pathway inhibitor, ...immunotherapy has gained even more interest as a potential novel treatment option for patients with HCC. This is due not only because of the failure of other treatment approaches in the past, but also because immunological mechanisms have been shown to play an important role during tumor development, growth, and treatment. Here we present a review of immunological mechanisms in the liver relevant for tumor progression and treatment. We summarize our current knowledge on immune activating and immune suppressing mechanisms during tumor initiation, development, and treatment. We try to explain the paradox of how inflammatory responses in a setting of chronic infection promote tumor development, while the primary aim of immunotherapy is to activate immunity. Finally we summarize recent advances in addition to providing an outlook for the immunotherapy of HCC.
Hepatocellular carcinoma is the third most common cancer worldwide. It is an inflammation-associated cancer. Multiple investigators have demonstrated that analysis of the tumor microenvironment may ...be used to predict patient outcome, indicating the importance of local immune responses in this disease. In contrast with other types of cancer, in which surgery, radiation, and systemic cytotoxic chemotherapies dominate the treatment options, in hepatocellular carcinoma locoregional treatments are widely applied. Such treatments induce rapid tumor cell death and antitumor immune responses, which may favor or impair the patients' outcome. Recent immunotherapeutic studies demonstrating promising results include trials evaluating intratumoral injection of an oncolytic virus expressing granulocyte macrophage colony-stimulating factor, glypican-3 targeting treatments, and anti-CTLA4 treatment. Although some of these novel approaches may provide benefit as single agents, there is a clear opportunity in hepatocellular carcinoma to evaluate these in combination with the standard modalities to more effectively harness the immune response.
Background: Gastroesophageal cancers (GECs) carry considerable morbidity and mortality, and demonstrate geographical histological variances in addition to molecular heterogeneity. Consequently, the ...immunogenicity of the different subtypes, which can predict the likelihood of immunotherapy response, can vary. Immune checkpoint inhibitor (ICI) therapy has transformed the treatment of many cancer types over the past decade but has been slower to gain a foothold in the treatment paradigm of GECs. Methods: This article reviews the existing evidence and use approvals for immunotherapies and immune-based treatments in GECs, in the neoadjuvant, adjuvant and metastatic disease settings. The challenges of and limitations to ICI application in current clinical practice are examined. Ongoing clinical trials and future directions of research are also considered. Conclusion: ICI therapy has become an established treatment option within GECs, both perioperatively and in advanced disease. However, nuances in terms of its use are not yet fully understood. Ongoing research proposes to broaden the application of immunotherapies in GECs with the potential to continue to improve outcomes.
Background
Checkpoint inhibitors have recently been approved for the treatment of patients with hepatocellular carcinoma (HCC). However, biomarkers, which will help identify patients responding to ...therapy, are missing. We recently tested the combination of anti-CTLA4 treatment (tremelimumab) with loco-regional therapy in patients with HCC and reported a partial response rate of 26%.
Methods
Here, we report updated survival analyses and results from our immune monitoring studies on peripheral blood mononuclear cells (PBMCs) and tumors from these patients.
Results
Tremelimumab therapy increased CD4
+
-HLA-DR
+
, CD4
+
PD-1
+
, CD8
+
HLA-DR
+
, CD8
+
PD-1
+
, CD4
+
ICOS
+
and CD8
+
ICOS
+
T cells in the peripheral blood of the treated patients. Patients with higher CD4
+
PD1
+
cell frequency at baseline were more likely to respond to tremelimumab therapy. PD-1 expression was increased on alpha fetal protein (AFP) and survivin-specific CD8 T cells upon tremelimumab treatment. An increase of tumor infiltrating CD3
+
T cells were also seen in these patients. Immunosequencing of longitudinal PBMC showed that one cycle of tremelimumab significantly decreased peripheral clonality, while no additional effects were seen after loco-regional therapy.
Conclusion
In summary, we observed a clear activation of T cell responses in HCC patients treated with tremelimumab and identified potential biomarkers which will help identify patients responding to immunotherapy with anti-CTLA4.
The purpose of the study was to assess the use of curative therapies for hepatocellular carcinoma (HCC) in the population. HCC treatment patterns were examined in Surveillance, Epidemiology, and End ...Results (SEER) 18 registries (28% of U.S.). Joinpoint regression analyses were performed to assess 2000‐2010 incidence trends by tumor size, count, and receipt of potentially curative treatments (transplantation, resection, and ablation). SEER‐Medicare data enabled evaluation of treatment patterns including receipt of sorafenib or transarterial chemoembolization (TACE) by HCC‐associated comorbidities. Diagnoses of tumors ≤5.0 cm in diameter significantly increased during 2000‐2010, surpassing diagnosis of larger tumors. Overall, 23% of cases received potentially curative treatment. Joinpoint models indicated incidence rates of treatment with curative intent increased 17.6% per year during 2000‐2005, then declined by −2.9% per year during 2005‐2010 (P < 0.001). Among HCC cases with a single tumor ≤5.0 cm and no extension beyond the liver, use of ablative therapy significantly increased during 2000‐2010. Use of invasive surgery for single tumors, regardless of size, significantly increased during the initial years of the decade, then plateaued. The group most likely to receive curative treatment in the SEER‐Medicare cases was patients with one, small tumor confined to the liver (657 of 1,597 cases, 41%), with no difference in treatment by hepatic comorbidity status (P = 0.24). A higher proportion of cases with reported liver‐associated comorbidities were, however, diagnosed with tumors ≤5.0 cm in diameter (1,745 0f 2,464, 71%) compared to patients with no reported comorbidities (996 of 2,596, 38%, P < 0.001). Conclusion: Although more HCC patients were diagnosed with early disease over time, the use of curative treatments in this patient group has recently plateaued. Efforts to identify and treat more eligible candidates for curative therapy could be beneficial. (Hepatology 2014;60:1637–1644)
In the West, recent decades have demonstrated an epidemiological trend towards esophago-gastric adenocarcinomas (EGAC), with considerable associated mortality. Historically, chemotherapy has ...represented the sole systemic treatment option in the advanced EGAC setting, in addition to complementing the role of surgery and radiotherapy in the case of localized disease. Immune checkpoint inhibitors (ICIs) represent a novel systemic therapeutic choice and have revolutionized the management of other malignancies, including melanoma and renal cell carcinomas. This article considers the rationale for ICIs in EGAC, reviews the evidence supporting their role in the current standard of care in EGAC, and briefly considers ongoing trials and future directions for the ICI class in EGAC.
The past 2 decades have witnessed progress in the management of metastatic colorectal cancer (mCRC) with more effective agents and better surgical, medical, and supportive care. While substantial ...progress has been made, much more must be achieved to prolong the lives of patients.
To conduct a systematic review to ascertain what percentage of the life expectancy gain in locally advanced and mCRC over the past 2 decades is due to novel therapies vs improvements in supportive care or secular trends and to thus inform treatment development strategies.
We searched Cochrane Controlled Trials Register, Medline, Embase, CancerLit, and Healthstar electronic databases for trials covering the period 1993 to 2015, scanned reference lists of articles, and searched recent conference abstracts. Ninety-six phase 3 trials and large (>50 patients) phase 2 trials in mCRC were examined. Outcomes evaluated in the experimental arms (EAs) and control arms (CAs) included overall response rate, stable disease, progression-free survival (PFS), and overall survival (OS).
Over the period covered by the studies, the OS in EAs increased at a mean (95% CI) rate of 0.80 (0.67-0.93) mo/y. Importantly, OS in the CAs improved 0.63 (0.51-0.75) mo/y, reflecting in part the use of experimental regimens in subsequent studies. Chemotherapy contributed only partly to the gains in OS, given that (1) mean (95% CI) improvements in PFS were only 0.31 (0.22-0.39) mo/y in the EAs and 0.23 (0.15-0.31) mo/y in CAs; (2) gains in survival not directly attributable to the protocol were greater than gains in PFS (0.46 0.36-0.57 mo/y in EAs and 0.39 0.29-0.49 mo/y in CAs; and (3) effects on OS were much lower in second-line trials (median interquartile range response rates, 8.6% 0%-11.0% in EAs and 7.5% 3.8%-12.8% in CAs) compared with first-line trials (39.5% 24.0%-50.2% for EAs and 29.4% 16.4%-39.4% for CAs).
The OS of patients with mCRC has improved gradually over the past 2 decades, with gains from chemotherapy occurring alongside gains from lead-time bias and improved locoregional approaches and supportive care. Gains from first-line therapies have been modest but consistent; however, gains from second-line therapies have been disappointing. We believe that future progress will be greater if emphasis is placed on enrolling patients in experimental trials to explore and develop alternative first-line regimens and better second-line therapies.
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